Noncanonical NF-κB signaling in dendritic cells is required for ATP-driven indoleamine 2,3-dioxygenase 1 induction through P2Y11 receptor

Extracellular ATP released from dying cells, including tumor cells, is a key mediator of inflammation and tolerance by binding to purinergic receptors on dendritic cells (DCs), resulting in inflammasome activation (via P2X7R), DC maturation (via P2Y11R), and indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human DCs has been poorly investigated. In this work, we aimed to investigate the ATP-driven molecular regulation of indoleamine-2,3-dioxygenase 1 expression via purinergic receptors and to provide an in-depth characterization of ATP-driven T regulatory cells induced by indoleamine-2,3-dioxygenase 1-expressing DCs. We identified P2Y11R as being responsible for ATP-driven indoleamine-2,3-dioxygenase 1 upregulation, and noncanonical NF-kB as a molecular pathway associated with ATP-dependent indoleamine-2,3-dioxygenase 1 induction through P2Y11R. Then, we investigated-but did not confirm-an involvement of inflammasome machinery through P2X7R in indoleamine-2,3-dioxygenase 1 upregulation. Finally, we evaluated the role of ATP catabolism via ATP ectonucleotidases, i.e. CD39 and CD73 and its main product adenosine, in regulating the generation of indoleamine-2,3-dioxygenase 1-driven T regulatory cells. We found that ATP-driven indoleamine-2,3-dioxygenase 1 upregulation is associated with CD73 upregulation and adenosine production. Additionally, ATP-treated indoleamine-2,3-dioxygenase 1-positive mature DCs induce PD-1-expressing bona fide suppressive T regulatory cells via adenosine A2AR. Collectively, a more in-depth understanding of ATP-driven immune-regulatory mechanisms through indoleamine-2,3-dioxygenase 1 regulation in human DCs leading to the induction of T regulatory cells can have clinical implications for the development of indoleamine-2,3-dioxygenase 1 inhibitors in cancer patients, especially in combination with immunotherapy such as an anti-CD73 or adenosine receptor agonist and immunogenic chemotherapy.